Biology:MRAS

From HandWiki
Revision as of 01:53, 11 February 2024 by TextAI (talk | contribs) (correction)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Short description: Protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3.[1][2][3] It is ubiquitously expressed in many tissues and cell types.[4] This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth.[5][6][7][8] The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[9]

Structure

Gene

The MRAS gene resides on chromosome 3 at the band 3q22.3 and includes 10 exons.[3] This gene produces 2 isoforms through alternative splicing.[10]

Protein

M-Ras is a member of the small GTPase superfamily under the Ras family, which also includes Rap1, Rap2, R-Ras, and R-Ras2 (TC21).[10] This protein spans a length of 209 residues. Its N-terminal amino acid sequence shares 60-75% identity with that in the Ras protein while its effector region is identical with that in Ras. M-Ras shares a similar structure with H-Ras and Rap2A with the exception of its switch 1 conformation when bound to guanosine 5'-(beta,gamma-imido)triphosphate (Gpp(NH)p). Of the two states M-Ras can switch between, M-Ras is predominantly found in its state 1 conformation, which does not bind Ras effectors.[11]

Function

The MRAS gene is expressed specifically in brain, heart, myoblasts, myotubes, fibroblasts, skeletal muscles, and uterus, suggesting a specific role of M-Ras in these tissue and cells.[12][13] M-Ras is involved in many biological processes by activating a wide variety of proteins. For instance, it is activated by Ras guanine nucleotide exchange factors and can bind/activate some Ras protein effectors.[14] M-Ras also weakly stimulates the mitogen-activated protein kinase (MAPK) activity and ERK2 activity, but modestly stimulates trans-activation from different nuclear response elements which bind transcription factors, such as SRF, ETS/TCF, Jun/Fos, and NF- kB/Rel.[13][15] M-Ras has been found to induce Akt kinase activity in the PI3-K pathway, and it may play a role in cell survival of neural-derived cells.[16] Moreover, M-Ras plays a crucial role in the downregulation of OCT4 and NANOG protein levels upon differentiation and has been demonstrated to modulate cell fate at early steps of development during neurogenesis.[17] M-Ras, induced and activated by BMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation.[18] M-Ras is involved in TNF-alpha-stimulated and Rap1-mediated LFA-1 activation in splenocytes.[19] More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of the actin cytoskeleton.[12] In addition, it is reported that M-Ras forms a complex with SCRIB and SHOC2, a polarity protein with tumor suppressor properties, and may play a key role in tumorigenic growth.[20]

Clinical significance

In humans, other members of the Ras subfamilies carry mutations in human cancers.[21] Furthermore, the Ras proteins are not only involved in tumorigenesis but also in many developmental disorders.[21] For instance, the Ras-related proteins appear to be overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin, and breast, as well as in lymphomas.[22][23][24][25] More currently, Ras family members such as R-RAS, R-RAS2 and also R-RAS3 have also been implicated as main factors in triggering neural transformation, with R-RAS2 as the most significant element.[26]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the MRAS gene, identified individuals at increased risk for both incidence and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[27]

Interactions

MRAS has been shown to interact with RASSF5[28] and RALGDS.[1][29]

References

  1. ↑ 1.0 1.1 "Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution". Oncogene 15 (22): 2675–85. November 1997. doi:10.1038/sj.onc.1201674. PMID 9400994. 
  2. ↑ "M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6". The Journal of Biological Chemistry 274 (34): 23850–7. August 1999. doi:10.1074/jbc.274.34.23850. PMID 10446149. 
  3. ↑ 3.0 3.1 "Entrez Gene: MRAS muscle RAS oncogene homolog". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=22808. 
  4. ↑ "BioGPS - your Gene Portal System". http://biogps.org/gene/22808/. [yes|permanent dead link|dead link}}]
  5. ↑ "R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells". Oncogene 19 (16): 2014–22. April 2000. doi:10.1038/sj.onc.1203530. PMID 10803462. 
  6. ↑ "MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate". Development 140 (16): 3311–22. August 2013. doi:10.1242/dev.091082. PMID 23863483. 
  7. ↑ "M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation". Experimental Cell Research 316 (3): 477–90. February 2010. doi:10.1016/j.yexcr.2009.09.028. PMID 19800879. 
  8. ↑ "An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth". Molecular Cell 52 (5): 679–92. December 2013. doi:10.1016/j.molcel.2013.10.004. PMID 24211266. 
  9. ↑ "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet 385 (9984): 2264–71. June 2015. doi:10.1016/S0140-6736(14)61730-X. PMID 25748612. 
  10. ↑ 10.0 10.1 "MRAS - Ras-related protein M-Ras precursor - Homo sapiens (Human) - MRAS gene & protein". https://www.uniprot.org/uniprot/O14807. 
  11. ↑ "Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases". The Journal of Biological Chemistry 280 (35): 31267–75. September 2005. doi:10.1074/jbc.M505503200. PMID 15994326. 
  12. ↑ 12.0 12.1 "Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton". Oncogene 15 (20): 2409–17. November 1997. doi:10.1038/sj.onc.1201416. PMID 9395237. 
  13. ↑ 13.0 13.1 "Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution". Oncogene 15 (22): 2675–85. November 1997. doi:10.1038/sj.onc.1201674. PMID 9400994. 
  14. ↑ "Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction". The Journal of Biological Chemistry 275 (45): 34901–8. November 2000. doi:10.1074/jbc.M005327200. PMID 10934204. 
  15. ↑ "M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6". The Journal of Biological Chemistry 274 (34): 23850–7. August 1999. doi:10.1074/jbc.274.34.23850. PMID 10446149. 
  16. ↑ "R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells". Oncogene 19 (16): 2014–22. April 2000. doi:10.1038/sj.onc.1203530. PMID 10803462. 
  17. ↑ "MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate". Development 140 (16): 3311–22. August 2013. doi:10.1242/dev.091082. PMID 23863483. 
  18. ↑ "M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation". Experimental Cell Research 316 (3): 477–90. February 2010. doi:10.1016/j.yexcr.2009.09.028. PMID 19800879. 
  19. ↑ "The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-alpha dependent regulation of integrin activation in splenocytes". Molecular Biology of the Cell 18 (8): 2949–59. August 2007. doi:10.1091/mbc.E07-03-0250. PMID 17538012. 
  20. ↑ "An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth". Molecular Cell 52 (5): 679–92. December 2013. doi:10.1016/j.molcel.2013.10.004. PMID 24211266. 
  21. ↑ 21.0 21.1 "Ras oncogenes: split personalities". Nature Reviews Molecular Cell Biology 9 (7): 517–31. July 2008. doi:10.1038/nrm2438. PMID 18568040. 
  22. ↑ "TC21 and Ras share indistinguishable transforming and differentiating activities". Oncogene 18 (12): 2107–16. March 1999. doi:10.1038/sj.onc.1202517. PMID 10321735. 
  23. ↑ "R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells". Oncogene 9 (11): 3281–8. November 1994. PMID 7936652. 
  24. ↑ "A human oncogene of the RAS superfamily unmasked by expression cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America 91 (16): 7558–62. August 1994. doi:10.1073/pnas.91.16.7558. PMID 8052619. Bibcode: 1994PNAS...91.7558C. 
  25. ↑ "A novel insertional mutation in the TC21 gene activates its transforming activity in a human leiomyosarcoma cell line". Oncogene 11 (7): 1255–60. October 1995. PMID 7478545. 
  26. ↑ "R-RAS2 overexpression in tumors of the human central nervous system". Molecular Cancer 12 (1): 127. 2013-01-01. doi:10.1186/1476-4598-12-127. PMID 24148564. 
  27. ↑ "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet 385 (9984): 2264–71. June 2015. doi:10.1016/S0140-6736(14)61730-X. PMID 25748612. 
  28. ↑ "The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1". Oncogene 21 (9): 1381–90. February 2002. doi:10.1038/sj.onc.1205192. PMID 11857081. 
  29. ↑ "M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line". Blood 94 (7): 2433–44. October 1999. doi:10.1182/blood.V94.7.2433.419k31_2433_2444. PMID 10498616. 

Further reading




Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:MRAS&oldid=3538628"